Rifaximin (INN; see The Merck Index, XIII Ed., 8304) is an antibiotic belonging to the rifamycin class of antibiotics, e.g., a pyrido-imidazo rifamycin. Rifaximin exerts its broad antibacterial activity, for example, in the gastrointestinal tract against localized gastrointestinal bacteria that cause infectious diarrhea, irritable bowel syndrome, small intestinal bacterial overgrowth, Crohn's disease, and/or pancreatic insufficiency. It has been reported that rifaximin is characterized by a negligible systemic absorption, due to its chemical and physical characteristics (Descombe J. J. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994)).
Rifaximin is described in Italian Patent IT 1154655 and EP 0161534, both of which are incorporated herein by reference in their entirety for all purposes. The EP patent discloses a process for rifaximin production using rifamycin O as the starting material (The Merck Index, XIII Ed., 8301). These patents generically describe purification strategies of rifaximin by crystallization in suitable solvents or solvent systems and summarily show in some examples that the resulting product can be crystallized from the 7:3 mixture of ethyl alcohol/water and dried both under atmospheric pressure and under vacuum. Neither patent discloses any experimental conditions, or further guidance for crystallization and drying or any indication that rifaximin exists in polymorphic forms. U.S. Pat. No. 7,045,620 B1 discloses the identification, characterization and process for obtaining polymorphic forms of rifaximin.
The identification and characterization of polymorphic forms, as well as the experimental conditions for obtaining polymorphs, is important for therapeutic compounds. Polymorphs of a compound can influence the pharmaco-toxicologic properties of the drug, such as bioavailability, solubility, stability, colour, compressibility, flowability and workability with consequent modification of the profiles of toxicological safety, clinical effectiveness and productive efficiency.
Rifaximin is approved for the treatment of pathologies caused by non-invasive strains as Escherichia coli, micro-organism which are not able to penetrate into GI mucosa and they remain in contact with the GI fluids.
Since 1980, when discovered, rifaximin appeared to be a non-adsorbed antibiotic and the published data on the bioavailability of rifaximin indicate that the maximum plasma level of rifaximin after oral administration appeared to be almost negligible, being in the range from 2 and 5 ng/ml (Descombe J. J. et al. Pharmacokinetic study of rifaximin after oral administration in healthy volunteers. Int J Clin Pharmacol Res, 14 (2), 51-56, (1994)).
This was considered an intrinsic property of the compound and the pharmaceutical develop was designed on this property.
As far as the drug safety profile is concerned, it should be reminded that in the therapeutic practice, antibiotics may cause bacterial resistance to the same or other similar antibiotics. This is particularly relevant to rifaximin because it belongs to the rifamycin family along with rifampicin, which is the standard of care for the treatment of tuberculosis. The current short course treatment for tuberculosis is a combination therapy involving four active pharmaceutical ingredients: rifampicin, isoniazid, ethambutol and pyrazinamide, with rifampicin playing a pivotal role. Therefore, any drug which jeopardizes the efficacy of the therapy by selecting for resistance to rifampicin would be harmful. (Kremer L. et al. “Re-emergence of tuberculosis: strategies and treatment”, Expert Opin. Investig. Drugs, 11 (2), 153-157, (2002)). Thus, it is possible that the use of rifaximin might induce the selection resistant strains of M. tuberculosis and cross-resistance to rifampicin. Polymorphic forms may provide a mechanism to avoid this negative event because the quantity of systemically absorbed rifaximin may be controllable through the use of polymorphic forms.